Major depressive disorder affects an estimated 340 million people worldwide. Depression is the most frequently diagnosed psychiatric disorder, and according to the World Health Organization, it is the fourth greatest public health problem. If left untreated, the effects of depression can be devastating, robbing people of the energy or motivation to perform everyday activities and, in some cases, leading to suicide. Symptoms of the disorder include feelings of sadness or emptiness, lack of interest or pleasure in nearly all activities, and feelings of worthlessness or inappropriate guilt. In addition to the personal costs of depression, the disorder also results in more than $40 billion in annual costs in the United States alone, due to premature death, lost productivity, and absenteeism.
Selective serotonin reuptake inhibitors (SSRIs) have had significant success in treating depression and related illnesses and have become among the most prescribed drugs since the 1980's. Some of the most widely known are fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram. Although they have a favorable side effect profile compared to tricyclic antidepressants (TCAs), they have their own particular set of side effects from the non-selective stimulation of serotonergic sites. They have a slow onset of action, often taking several weeks to produce their full therapeutic effect. Furthermore, they are effective in less than two-thirds of patients.
SSRIs work by blocking the neuronal reuptake of serotonin, which tends to increase the concentration of serotonin in the synaptic space, and thus increase the activation of postsynaptic serotonin receptors. Although a single dose of a SSRI can inhibit the neuronal serotonin transporter and thus would be expected to increase synaptic serotonin, clinical improvement is achieved only after long-term treatment. It has been suggested that the delay in onset of antidepressant action of the SSRIs is the result of an increase in serotonin levels in the vicinity of the serotonergic cell bodies. This excess serotonin activates somatodendritic autoreceptors, 5-HT1A receptors, which reduces cell firing activity and, in turn, causes a decrease in serotonin release in major forebrain areas. This negative feedback limits the increment of synaptic serotonin that can be induced by antidepressants acutely. Over time, the somatodendritic autoreceptors become desensitized allowing the full effect of the SSRIs to be expressed in the forebrain. This time period corresponds to the latency for the onset of antidepressant activity [Perez, V., et al., The Lancet, 349:1594-1597 (1997)].
In contrast to the SSRIs, a 5-HT1A agonist or partial agonist acts directly on postsynaptic serotonin receptors to increase serotonergic neurotransmission during the latency period for the SSRI effect. Accordingly, the 5-HT1A partial agonists buspirone and gepirone [Feiger, A., Psychopharmacol. Bull., 32 (4), 659-665 (1996), Wilcox, C., Psychopharmacol. Bull, 32 (93), 335-342 (1996)] and the 5-HT1A agonist flesinoxan [Grof, P., International Clinical Psychopharmacology, 8 (3), 167-172 (1993)] have shown efficacy in clinical trials for the treatment of depression. Furthermore, such agents would also stimulate the somatodendritic autoreceptors, thus hastening their desensitization and decreasing the SSRI latency period. An agent with a dual mechanism of antidepressant action, i.e. increases serotonin levels by blocking neuronal reuptake of serotonin and desensitizes somaticdendritic autoreceptors, would be expected to have greater efficacy and thus reduce the number of patients refractory to treatment. Indeed, buspirone augmentation to standard SSRI therapy has been shown to produce marked clinical improvement in patients initially unresponsive to standard antidepressant therapy [Dimitriou, E., J. Clinical Psychopharmacol., 18(6), 465-469 (1998)].
Lacking from the current therapy regime, however, is a single compound that effectively displays the dual mechanism of antidepressant action, i.e., one that not only inhibits or blocks serotonin reuptake (and thereby increases the levels of serotonin in the synapse), but also antagonizes the 5-HT1A receptors (and thereby reduces the latency period). The present invention is directed to these, as well as other, important ends.